Transition-metal free 2-arylbenzoxazole formation from aryl amides and cyclohexanones

Article abstract of DOI:10.1039/c4gc01572j

A transition-metal-free method for the synthesis of 2-arylbenzoxazoles from readily available cyclohexanones and benzamides is described. The combined use of KI, p-TsOH and DMSO significantly improved the reaction yields. Non-aromatic cyclohexanones were smoothly dehydrogenated and acted as the aryl source using oxygen as the oxidant.

Full text of DOI:10.1039/c4gc01572j

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Transition-metal free 2-arylbenzoxazole formation
from aryl amides and cyclohexanones†
Cite this: DOI: 10.1039/c4gc01572j
Received 13th August 2014,
Accepted 28th August 2014
a
a
a
a
a,b
Xiangxiang Cao, Xiufang Cheng, Yang Bai, Saiwen Liu and Guo-Jun Deng*
DOI: 10.1039/c4gc01572j
www.rsc.org/greenchem
A transition-metal-free method for the synthesis of 2-arylbenz- been made in the development of efficient procedures to con-
oxazoles from readily available cyclohexanones and benzamides is struct these important compounds. The classic methods to
described. The combined use of KI, p-TsOH and DMSO signifi- prepare arylbenzoxazoles are mainly based on the conden-
cantly improved the reaction yields. Non-aromatic cyclohexanones sation of 2-aminophenols with carbonyl-containing substrates
2
were smoothly dehydrogenated and acted as the aryl source using in the presence of strong acids or oxidants (Scheme 1, a). The
oxygen as the oxidant.
metal-catalyzed cyclization of o-haloanilides afforded an
alternative procedure for the facile synthesis of aryl-substituted
benzoxazoles (Scheme 1, b). Simple N-arylbenzamides were
Aryl-substituted benzoxazoles are an important class of hetero-
cycles that have many applications in natural products, func-
tional materials and pharmaceutical drugs. Great effort has
3
also successfully employed for this kind of reaction via
transition-metal-catalyzed tandem C–H functionalization/
1
4
C–O bond formation. In recent years, the direct arylation of
benzoxazole C–H bonds has stimulated considerable interest.
a
Table 1 Optimization of the reaction conditions
b
Entry
Additive
NIS
Acid
Oxidant
Yield (%)
1
2
3
4
5
6
7
8
9
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
4
30
27
73
49
36
5
28
51
57
30
24
70
72
42
52
42
I
2
KI
KI (0.6 eq.)
KI (2.0 eq.)
KI
KI
KI
KI
KI
KI
KI
KI
KI
KI
KI
TFA
CH
3
SO
SO
CO
3
H
10
11
12
13
14
CF
3
3
H
CH
3
2
H
Scheme 1 Various procedures for 2-arylbenzoxazole synthesis.
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
2
Ph SO
c
d
e
f
DMSO
DMSO
DMSO
DMSO
a
15
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry
1
1
6
7
of Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China.
E-mail: gjdeng@xtu.edu.cn; Fax: (+86)-731-58292251
b
a
Key Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Conditions: 1a (0.3 mmol), 2a (0.2 mmol), additive (1.2 equiv.), acid
Chinese Academy of Sciences, Beijing 100080, China
†
(1.0 equiv.), solvent (toluene/o-dichlorobenzene = 4 : 1, 1.0 mL), DMSO
b
c
Electronic supplementary information (ESI) available. See DOI: 10.1039/
(1.0 equiv.), 160 °C, 30 h under oxygen. GC yield based on 2a. DMSO
d e f
c4gc01572j
(2.0 equiv.). In toluene. In o-dichlorobenzene. Under air.
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Various 2-aryl-substituted benzoxazoles were synthesized from under mild reaction conditions using oxygen as the sole
5
11
benzoxazoles and aryl halides as well as other coupling part- oxidant. We and others successfully trapped the dehydro-
6
12
ners. Under oxidative reaction conditions, simple arenes were genation intermediates for further construction of C–C,
able to couple with benzoxazoles via transition-metal catalyzed C–N, C–O and C–S bonds. In these procedures, cyclo-
double C–H activation (Scheme 1, c).
1
3
14
15
7
hexanones were used as the aryl source via a dehydrogenation–
Although there are other methods available for the con- tautomerization sequence. In most cases, molecular oxygen
8
struction of aryl-substituted benzoxazoles, most of them are could act as an efficient hydrogen acceptor. Due to the impor-
based on two aromatic substrates in the presence of transition- tance of 2-arylbenzoxazoles in pharmaceutical drugs and other
metal catalysts. Aryl-substituted benzoxazole formation using biologically active compounds, it is highly desirable to explore
cheap and non-aromatic coupling partners (one or two) under new procedures to prepare them using stable and readily
transition-metal-free conditions is rare and challenging. Cyclo- available raw materials. Herein, we describe a novel method
hexanones are commercially available, stable and widely used for 2-arylbenzoxazole formation from readily available cyclo-
9
as raw materials to prepare other important bulk chemicals.
hexanones and benzamides without using a transition-metal
Various methods have also been pursued to convert cyclo- catalyst (Scheme 1, d).
hexanones into phenols via a dehydrogenation procedure, but
To obtain the optimized conditions, the readily available
reactions of this type usually require strong oxidants, such as benzamide (1a) and cyclohexanone (2a) were used as the
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), need harsh model substrates. When cyclohexanone reacted with 1.5 equi-
reaction conditions (>200 °C), or use stepwise procedures valents of benzamide in the presence of dimethyl sulfoxide
1
0
that severely limit functional group compatibility. Recently, (DMSO) and p-toluenesulfonic acid (p-TsOH), the corres-
the Stahl group reported palladium-catalyzed procedures ponding product 2-phenylbenzoxazole (3a) was formed in 4%
to convert non-aromatic cyclohexanones into phenols or cyclo- yield as measured by GC (Table 1, entry 1). Several iodide-
hexenones via a dehydrogenation–tautomerization strategy containing additives were then screened for this reaction
a
Table 2 Reaction of 1a with various cyclohexanones
b
Entry
Cyclohexanone
Product
Yield (%)
1
1
2
3
4
5
6
7
8
R = H
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
71
73
62
64
74
76
82
68
1
R = Me
1
R = Et
1
R = isopropyl
1
R = n-pentyl
1
R = tert-pentyl
1
R = Ph
2g
2h
3g
3h
1
R = CO
2
Et
c
9
2i
5
1
0
1
2j
3a
52
1
2k
80 (3k : 3k′ = 2 : 1)
a
Conditions: 1a (0.3 mmol), 2a (0.2 mmol), additive (1.2 equiv.), acid (1.0 equiv.), solvent (toluene/o-dichlorobenzene = 4 : 1, 1.0 mL), DMSO
b
c
(1.0 equiv.), 160 °C, 30 h under oxygen. Isolated yield based on 2a. GC yield based on 2a.
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(entries 2–4). The reaction yields could be smoothly improved various cyclohexanones with substituents at the para position
by using 1.2 equiv. of iodide-containing additives. Among of the carbonyl group smoothly reacted with benzamide to
them, KI showed the best efficiency and its use afforded the give the expected products in good yields (entries 2–8). The
expected product 3a in 73% yield (entry 4). Decreasing or chain length of alky substituents did not make much differ-
increasing the amount of KI significantly decreased the reac- ence on the reaction yields. When 4-methylcyclohexanone (2b)
tion yield (entries 5 and 6). Only 5% yield was observed when and 4-pentylcyclohexanone (2e) reacted with benzamide, the
the reaction was performed without an acid additive (entry 7). corresponding products 3b and 3e were obtained in 73% and
The use of other organic acids, such as trifluoroacetic acid, 74% yields, respectively. The presence of a phenyl group on
methane sulfonic acid, trifluoromethane sulfonic acid and the cyclohexanone ring slightly improved the reaction yield,
acetic acid, all decreased the reaction efficiency (entries 8–11). and 3g was obtained in 82% yield when 4-phenylcyclo-
A control experiment showed that DMSO was necessary to get hexanone (2g) was used (entry 7). The active ester group was
satisfactory yield, and only 24% yield was obtained in its well tolerated under the optimized reaction conditions to give
absence (entry 12). Slightly lower yield was obtained when the expected product 3h in 68% yield (entry 8). Unfortunately,
DMSO was replaced by diphenyl sulfoxide (entry 13). Increas- only 5% GC yield of 3i was observed when the methyl group
ing the amount of DMSO to 2.0 equivalents did not signifi- was located at the ortho position of cyclohexanone due to the
cantly improve the reaction yield (entry 14). A mixture solvent steric effect (entry 9). When 2-chlorocyclohexanone (2j) was
was necessary to get satisfactory yield and the use of a single employed as the substrate, 3a was obtained in 52% yield and
solvent such as toluene or o-dichlorobenzene resulted in lower no chloro-containing product (3j) could be observed (entry 10).
yield (entries 15 and 16). The reaction yield dramatically When the methyl group was located at the meta position, two
decreased to 42% when oxygen was replaced by air (entry 17).
isomers were obtained in a combined yield of 80% (entry 11).
Next, the reaction of benzamide 1a with various cyclo-
The reaction of various benzamides with cyclohexanone 2a
hexanones was conducted under the optimal conditions. The was also investigated (Table 3). In general, benzamides with
corresponding results are summarized in Table 2. In general, different substituents at the para position could smoothly
a
Table 3 Reaction of 2a with various aryl amides
b
Entry
Aryl amide
Product
Yield (%)
2
1
2
3
4
5
6
R = CH
3
1b
1c
1d
1e
1f
3l
75
77
71
82
83
76
2
R = tert-butyl
3m
3n
3o
3p
3q
2
R = OCH
3
2
R = F
2
R = Cl
2
R = Br
1g
7
1h
64
8
1i
67
9
1j
51
a
Conditions: 1a (0.3 mmol), 2a (0.2 mmol), additive (1.2 equiv.), acid (1.0 equiv.), solvent (toluene/o-dichlorobenzene = 4 : 1, 1.0 mL), DMSO
b
(1.0 equiv.), 160 °C, 30 h under oxygen. Isolated yield based on 2a.
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p-TsOH and KI significantly improved the reaction yields.
The dehydrogenated intermediates of cyclohexanones were
successfully trapped and used as an efficient aryl source. The
condensation, tautomerization, cyclization and dehydrogena-
tion were realized in one pot under an oxygen atmosphere.
Alkyl, halogen, hydroxyl and ester were all compatible with the
optimized reaction conditions. The mechanism and synthetic
applications of this reaction are under investigation.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21172185, 21372187), the Hunan Provin-
cial Innovative Foundation for Postgraduate (CX2013B269), the
New Century Excellent Talents in University from Ministry of
Education of China (NCET-11-0974) and the Research Fund for
the Doctoral Program of Higher Education of China, Ministry
of Education of China (20124301110005).
Scheme 2 Control experiments and the possible pathway.
Notes and references
react with cyclohexanone to generate the expected products in
good yields (entries 1–6). When fluoro and chloro substituents
were present, the corresponding products 3o and 3p were
obtained in 82% and 83% yields, respectively (entries 4 and 5).
A slightly lower yield was achieved when 4-bromobenzamide
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salicylamide (1i) which contains an active hydroxyl group also
reacted with 2a to afford the expected product in 67% yield
(
entry 8). To our delight, the desired product (3t) was obtained
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(
conditions. Intermediate 4a was obtained as the major
product when the reaction was stopped in 2 h (Scheme 2, 1).
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necessary for this conversion (Scheme 2, 2). Although the exact
mechanism is not clear, a possible reaction pathway is illus-
trated in Scheme 2 based on our observation and other litera-
1
3f,16
ture
(Scheme 2, 3). Protonation of 2a generates an
intermediate A which undergoes α-iodination to generate
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1
6,13b,15c
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